Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
  • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/12—Antidiarrhoeals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates to a new method of use for 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b] [1,5]benzodiazepine for treating certain gastrointestinal conditions.
• the compound 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b] [1,5]benzodiazepine can be useful for treating certain gastrointestinal conditions.
• One such gastrointestinal condition is irritable bowel syndrome which is characterized by abdominal pain, alteration of bowel habits, or a combination of the two. Irritable bowel syndrome is expensive and afflicts between 14% to 22% of the population. Gastroenterology , 591-595, 100 (1991).
• This invention provides a method for treating a mammal, including a human, suffering from or susceptible to a Functional Bowel Disorder, which comprises administering an effective amount of 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b] [1,5]benzodiazepine, or an acid addition salt thereof.
• treating includes prophylaxis of the named condition or amelioration or elimination of the condition once it has been established.
• the term “Functional Bowel Disorder” refers to a functional gastrointestinal disorder manifested by (1) abdominal pain and/or (2) symptoms of disturbed defecation (urgency, straining, feeling of incomplete evacuation, altered stool form [consistency] and altered bowel frequency/timing) and/or (3) bloating (distention).
• the term “Functional Bowel Disorder” includes but is not limited to irritable bowel syndrome, hypermotility, ichlasia, hypertonic lower esophogeal sphinctor, tachygastria, constipation, hypermotility associated with irritable bowel syndrome.
• Abnormal bowel function includes diarrhea, constipation, mucorrhea, and pain or discomfort over the course of the sigmoid colon. Such disorders are influenced by psychological factors and stressful life situations.
• IBS The Functional Bowel Disorder, Irritable Bowel Syndrome
• the compound 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b] [1,5]benzodiazepine has antimuscarinic activity, 5-HT 2B receptor activity, and is denoted for use in the treatment of certain gastrointestinal conditions.
• the compound is useful for the treatment of Functional Bowel Disorders including, but not limited to, irritable bowel syndrome, gastric hypermotility, and related conditions.
• 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b] [1,5]benzodiazepine is used for the treatment of irritable bowel syndrome or gastric hypermotility disorder.
• 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b] [1,5]benzodiazepine is used for the treatment of irritable bowel syndrome.
• the 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b] [1,5]benzodiazepine can be used for the treatment of gastrointestinal conditions both in the free base and acid addition salt forms.
• the acid addition salts are preferably the pharmaceutically acceptable, non-toxic addition salts with suitable acids, such as those of inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or of organic acids, such as organic carboxylic acids, for example glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric or lactic acid, or organic sulphonic acids for example methane-sulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, toluene-p-sulphonic or naphthalene-2-sulphonic acid.
• suitable acids such as those of inorganic acids, for example hydrochloric, hydrobromic, nitric,
• 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b] [1,5]benzodiazepine has useful central nervous system activity. This activity has been demonstrated in animal models using well-established procedures.
• 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b] [1,5]benzodiazepine has been found to have a favorable profile of activity in a number of in vitro binding assays, designed to measure the degree of binding to neural receptors.
• the compound has an IC50 of less than 1 ⁇ M in the 3H-QNB binding assay described by Yamamura, HI and Snyder, SH in Proc.Nat.Acad.Sci. USA 71 1725 (1974) indicating that it has antimuscarinic-anticholinergic activity.
• the compound shows its greatest activity at the 5-HT-2 receptor in that it displaces H-spiperone from binding sites in the rat frontal cortex (Peroutka, SJ and Snyder, SH Mol. Pharmacol. 16 687 (1979)) at low nanomolar concentrations.
• the compound is also active at the 5-HT-1C receptor.
• Membrane preparation from transformed cells Suspension cells expressing the cloned human 5-HT 2B receptor were processed as previously described for the cloned rat 5-HT 2B receptor. Kursar, J. D., D. L. Nelson, D. B. Wainscott, M. L. Cohen, and M. Baez, Mol. Pharmacol. 42 : 549-557 (1992). The cells were harvested by centrifugation at 2,200 x g for 15 min at 4°C. Membranes for the binding assays were prepared by vortexing the pellet in 50 mM Tris-HCl, pH 7.4 (0.5 x 109 cells/30 ml). The tissue suspension was then centrifuged at 39,800 x g for 10 min at 4°C.
• [3H]5-HT binding studies were automated using a Biomek 1000 (Beckman Instruments, Fullerton, CA) and were performed in triplicate in 0.8 ml total volume. Membrane suspension, 200 ⁇ l, (0.04-0.27 mg protein) and 200 ⁇ l of drug dilution in water were added to 400 ⁇ l of 67 mM Tris-HCl, pH 7.4, containing [3H]5-HT, pargyline, CaCl2, and L-ascorbic acid. Final concentrations of pargyline, CaCl2 and L-ascorbic acid were 10 ⁇ M, 3 mM and 0.1%, respectively.
• Tubes were incubated at 37°C for 15 min (binding equilibria were verified for both of these conditions), then rapidly filtered using a Brandel cell harvester (Model MB-48R; Brandel, Gaithersburg, MD) through Whatman GF/B filters which were presoaked in 0.5% polyethylenimine and precooled with ice-cold 50 mM Tris-HCl, pH 7.4. The filters were then washed rapidly four times with one ml ice-cold 50 mM Tris-HCl, pH 7.4.
• a Brandel cell harvester Model MB-48R; Brandel, Gaithersburg, MD
• the amount of [3H]5-HT trapped on the filters was determined by liquid scintillation spectrometry (Ready Protein and Beckman LS-6000 IC, Beckman Instruments) Saturation curves for [3H]5-HT binding were determined for best fit to a one-site or a two-site binding model using a partial F-test. De Lean, A., A. A. Hancock, and R. J. Lefkowitz, Mol. Pharmacol. 21 : 5-16 (1981).
• the IC50 values from the competition assays, the binding parameters for the IP3 standard curve and the EC50 and E max values from the IP3 assays were determined by nonlinear regression analysis of four parameter logistic equations (Systat, Systat Inc, Evanston, IL). De Lean, A., A. A. Hancock, and R. J. Lefkowitz, Mol. Pharmacol. 21 : 5-16 (1981). The IC50 values were converted to K i values using the Cheng-Prusoff equation. Cheng, Y., and W. H. Prusoff, Biochem . Pharmacol . 22 : 3099-3108 (1973).
• Tissues are mounted in organ baths containing 10 mL of modified Krebs' solution of the following composition (millimolar concentrations): NaCl, 118.2, KCl, 4.6; CaCl2 ⁇ H2O, 1.6; KH2PO4, 1.2; MgSO4, 1.2; dextrose, 10.0; and NaHCO3, 24.8.
• Tissue bath solutions are maintained at 37°C and equilibrated with 95% O2 and 5% CO2.
• Tissues are placed under optimum resting force (4 g) and are allowed to equilibrate for approximately 1 hour before exposure to the test compound. Isometric contractions are recorded as changes in grams of force on a Beckman Dynograph with Statham UC-3 transducers.
• Noncumulative contractile concentration-response curves for serotonin and other agonists in the fundus are obtained by a stepwise increase in concentration after washing out the preceding concentrations every 15-20 minutes. Each agonist concentration remains in contact with the tissue for approximately 2 minutes and maximum response to each compound concentration is measured . ED50 values are taken as the concentration of agonist that produces half-maximal contraction. After control responses are obtained, tissues are incubated with an appropriate concentration of buffer or antagonist for 1 hour. Responses to serotonin are then repeated in the presence of an antagonist. Concentration responses utilize only one agonist and one antagonist concentration per tissue. In general, successive agonist responses in the presence of buffer treatment are unaltered (average dose ratio was 1.28 +/- 0.21).
• Sprague-Dawley rats (200-250g; Laboratory Supply, Indianapolis, IN) are sacrificed by cervical dislocation and 8 cm segment of distal colon is removed and washed in ice cold modified Kreb's solution of the following composition (millimolar): NaCl, 118.2; KCl, 4.6; CaCl2. H2O, 1.6; KH2PO4, 1.2; MgSO4, 1.2; dextrose, 10.0; and NaHCO3, 24.8.
• the colon is mounted on a glass rod and the longitudinal muscle layer with attached myenteric plexi is removed and mounted in organ baths, containing above described Kreb's solution maintained at 370C and equilibrated with 95% 02 and 5% CO2.
• Tissues are placed under 2 g tension and allowed to stabilize for 1 hour. Isometric contractions are recorded as changes in grams of force using grass FT03 transducers and MI2- computerized dynograph system. Cumulative concentration-response curves for serotonin were obtained by a stepwise increase in concentration after washing out the preceding concentration for 10-15 minutes. Each agonist concentration remains in contact with the tissue for 5 minutes. Maximum response to each concentration is determined and digitized. EC50 values are taken as the concentration of agonist that produced half maximal contraction. After control responses are obtained, tissues are incubated with an appropriate concentration of antagonist for 15 minutes. Response to serotonin are then repeated in the presence of an antagonist. Concentration-response utilizes only one concentration of antagonist per tissue.
• 5-HT 2B receptor antagonists are potent competitive inhibitors of serotonin-induced contraction of the colon. Such compounds can act to normalize gastrointestinal motility and be useful in the treatment of Functional Bowel Disorders.
• the profile of activity observed in the in vitro receptor binding assays indicates that the compound is effective for the treatment of Functional Bowel Disorders.
• the 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b] [1,5]benzodiazepine compound is effective over a wide dosage range, the actual dose administered being dependent on the condition being treated.
• dosages of from 0.25 to 30 mg, preferably from 1 to 20 mg, per day may be used.
• a once a day dosage is normally sufficient, although divided doses may be administered.
• a dose range of from 1 to 20 mg, preferably 2.5 to 15 mg per day is suitable.
• the 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b] [1,5]benzodiazepine compound will normally be administered orally or by injection and, for this purpose, it is usually employed in the form of a pharmaceutical composition.
• compositions comprising 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b] [1,5] benzodiazepine, or a pharmaceutically acceptable acid addition salt thereof, as active ingredient associated with a pharmaceutically acceptable carrier may be prepared.
• a pharmaceutically acceptable carrier for example, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
• the carrier serves as a diluent, it may be solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient.
• the active ingredient can be adsorbed on a granular solid container for example in a sachet.
• suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl-and propyl-hydroxy-benzoate, talc, magnesium stearate or mineral oil.
• the compositions of the invention may, if desired, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
• compositions for the treatment of gastrointestinal conditions may be formulated as tablets, capsules, injection solutions for parenteral use, gel or suspension for transdermal delivery, suspensions or elixirs for oral use or suppositories.
• the compositions are formulated in a unit dosage form, each dosage containing from 0.25 to 30 mg, more usually 1 to 20 mg, of the active ingredient.
• the unit dosage form may contain from 0.25 to 200 mg of the active ingredient.
• a preferred formulation of the invention is a capsule or tablet comprising 0.25 to 30 mg or 1 to 20 mg of active ingredient together with a pharmaceutically acceptable carrier therefor.
• a further preferred formulation is an injection which in unit dosage form comprises 0.25 to 30 mg or 1 to 20 mg of active ingredient together with a pharmaceutically acceptable diluent therefor.
• a pulvule formulation is prepared by blending the active with silicone starch, and filling it into hard gelatin capsules.
• Per 300 mg capsule 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b] [1,5]benzodiazepine 5.0 mg Silicone 2.9 mg Starch flowable 292.1 mg
• a tablet formulation is made by granulating the active with appropriate diluent, lubricant, disintegrant and binder and compressing 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b] [1,5]benzodiazepine 5.0 mg Magnesium stearate 0.9 mg Microcrystalline cellulose 75.0 mg Povidone 15.0 mg Starch, directly compressible 204.1 mg
• An aqueous injection of active compound is prepared as a freeze-dried plug, for reconstitution with diluent in a suitable, sterile 25 ml vial before use (to a total volume of 10 ml).
• 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b] [1,5]benzodiazepine Mannitol, N Hydrochloric acid and/or N sodium hydroxide to adjust pH to 5-5.5.
• 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b] [1,5]benzodiazepine 20.0 mg Mannitol N Hydrochloric acid and/or N sodium hydroxide to adjust pH to 5-5.5. 20.0 mg
• a controlled release injection for intramuscular injection is formed from a sterile suspension of micronised active in an oleaginous vehicle.
• 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b] [1,5]benzodiazepine 65.0 mg Aluminium stearate 0.04 mg Sesame oil 2 ml
• a capsule formulation is prepared by blending the active with silicone starch and starch, and filling it into hard gelatine capsules.
• Per 290 mg capsule 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b] [1,5]benzodiazepine 2.5 mg Starch flowable with 0.96% silicone 220 217.5 mg Starch flowable 70.0 mg

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• 1994
  • 1994-06-03 US US08/253,658 patent/US5457101A/en not_active Expired - Fee Related
• 1995
  • 1995-05-29 NZ NZ272231A patent/NZ272231A/en unknown
  • 1995-05-29 ZA ZA954358A patent/ZA954358B/xx unknown
  • 1995-05-29 TW TW084105417A patent/TW372872B/zh active
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  • 1995-05-30 NO NO952130A patent/NO306977B1/no not_active IP Right Cessation
  • 1995-05-30 CA CA002150517A patent/CA2150517A1/fr not_active Abandoned
  • 1995-05-31 AU AU20424/95A patent/AU684924B2/en not_active Ceased
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  • 1995-06-02 EP EP95303788A patent/EP0685233B1/fr not_active Expired - Lifetime
  • 1995-06-02 JP JP7136571A patent/JPH07330608A/ja not_active Withdrawn
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